The proposed research will be performed in a guinea pig model of experimental auto-immune glomerulonephritis in which animals with deposits of autologous antibody to glomerular basement membrane (GBM) develop sustained heavy proteinuria. In most proteinuria animals anti- GBM antibody deposits are not accompanied by deposits of BlC-BlA (C3) in vivo, and deposited, circulating and eluted anti-GBM antibody does not fix C3 in vitro. The focal, non-inflammatory histologic lesion in proteinuric animals is accompanied by a diffuse decrease in staining for glomerular sialoprotein and a unique electron-lucent ultra structural GBM lesion. The studies proposed will further define the immunopathogenesis of this apparently complement-independent glomerular lesion and investigate how this immunologic mechanism mediates alterations in glomerular permeability by: 1. Using eluted antibody to a) transfer the lesion to normal recipients, and b) evaluate the role of complement in mediating glomerular injury using recipients depleted of, or deficient in, selected complement components and neutrophils (active immunization of C4 deficient animals will also be carried out). 2. Establishing the role of the morphologic GBM lesion is altering GBM permeability using electron dense tracer molecules. 3. Contrasting this lesion to that mediated by complement-dependent nephrotoxic antibody. 4. Defining the sequence in which anti-GBM antibody of the gamma 1 and gamma 2 subclasses deposit, sialoprotein alterations occur, ultrastructural GBM lesions appear, and the GBM becomes permeable to various serum proteins. 5. Using the results obtained in #4 to evaluate the effect of agents which inhibit the coagulation system, vasoactive amines and kinin activation on development of the golmerular lesion, and 6. Determining whether antibody induces GBM damage in this model directly or by interfering with epithelial cell function thereby causing secondary changes in GBM structure and function.